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Site-Specific Antibody Conjugation for ADC and Beyond
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
The site-specific antibody conjugation has been applied for preparing immunoconjugates against other diseases such as autoimmune diseases and atherosclerosis. A highly potent phosphodiesterase 4 (PDE4) inhibitor, GSK256066, was site-specifically coupled to a human anti-CD11a through an unnatural amino acid, pAcF, introduced at HC-A122 with DAR at ~2 [69]. PDE4 is a cAMP phosphodiesterase widely expressed in a variety of cells and some small molecule PDE4 inhibitors showed wide-ranging preclinical efficacy in autoimmune diseases with a few being approved by regulatory agencies for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects have impeded their broader therapeutic application. The site-specific conjugation of pan-immune cell targeting human anti-CD11a with GSK256066 resulted in an immunoconjugate that was rapidly internalized into immune cells and suppressed lipopolysaccharide (LPS)-induced TNFa secretion in primary human monocytes. In another study, a liver X receptor (LXR) agonist was site-specifically conjugated to pAcF at HC-A122 of anti-CD11a [70]. Liver X receptor agonists have been explored as potential treatments for atherosclerosis and other diseases based on their ability to induce reverse cholesterol transport and suppress inflammation. However, this therapeutic potential has been limited by on-target adverse effects in the liver mediated by excessive lipogenesis after the interaction of the ligand with LXR-a. To prevent the adverse effect, the aminoooxy-modified LXR agonist was coupled to pAcF in anti-CD11a for selective delivery of the agonist to monocytes/macrophages while sparing hepatocytes. The anti-CD11a IgG-LXR agonist immunoconjugate induced LXR activation specifically in human THP-1 monocyte/macrophage cells in vitro with EC50 at nM range, but had no significant effect in hepatocytes, indicating that the payload delivery was CD11a-mediated. This approach represents a fundamentally different strategy that uses tissue targeting to overcome the limitations of LXR agonists for potential use in treating atherosclerosis.
Hyperlipidemia and male infertility
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Zainab Bubakr Hamad Zubi, Hamad Abdulsalam Hamad Alfarisi
Liver X receptors (LXRs) are nuclear receptors with transcription factor characteristics [73]. They are stimulated by oxysterols, metabolic derivatives or oxidized forms of cholesterol. They have important roles in controlling of lipid, cholesterol and metabolic homeostasis and regulation of proliferation, differentiation, inflammation and reproduction [74]. There are two isoforms of LXRs; LXRα (NR1H3) which are expressed mainly in the tissues that have important activities in lipid metabolism such as liver and brown adipose tissue. The second isoform is LXRβ (NR1H2) which is ubiquitously represented [75]. Several studies have emphasized on the importance of LXRs in male fertility. Liver X receptors Knockout (LXRα; β−/−) male mice demonstrated a dramatic reduction in the fertility capacity with aging, where there is abrupt fertility reduction around the age of 6 months followed by a complete loss of mature germ cells at the age of 10 months [Frenoux et al., 8; 76]. Liver X receptors alpha (LXRα) are abundantly expressed in Leydig and germ cells; whereas, LXRβ are mainly expressed in Sertoli cells and to a less extent in the germ cells [77]. Loss of LXRβ disrupts cholesterol homeostasis resulting in an accumulation of cholesterol esters in the Sertoli cells, which leads ultimately to testicular destruction that is more severe in the absence of the two isoforms of LXRs [76].